Acacetin and Chrysoeriol: A Short Review of the Chemistry, Plant Sources, Bioactivities and Structure-Activity Relationships of these Methylated Flavones doi.org/10.26538/tjnpr/v6i1.1
Main Article Content
Abstract
Flavonoids are plant secondary metabolites that are well-known for their bioactivities. In this article, the chemistry, plant sources, bioactivities and structure-activity relationships of acacetin (ACT) and chrysoeriol (CSE) are reviewed. Of these two flavones, only ACT has been reviewed but not CSE. Sources of information cited were from Google Scholar, PubMed, PubMed Central, Science Direct, Web of Science, J-Stage, PubChem and Directory of Open Access Journals (DOAJ). The criteria used for selection of articles are based on topics rather than period of coverage, although recent references accord higher priority. Flavones, a class of flavonoids, have a C2–C3 double bond and a 4-carbonyl group but lack the C3 hydroxyl group at ring C. ACT and CSE are lesser-known methylated flavones with hydroxyl groups at C5 and C7 of ring The methoxy group of ACT is at C4' while that of CSE is at C3'. Found in many plant species, ACT and CSE have generated much research interest because of their diverse pharmacological activities, notably, their anti-cancer properties. The anti-cancer effects and molecular mechanisms of ACT towards lung, liver, gastric, prostate, breast and squamous cancer cells including leukaemia have been reported. Studies have shown that CSE inhibited breast, lung and pancreatic cancer cells including myeloma. Other bioactivities and structure-activity relationships of ACT and CSE are also briefly mentioned. Some areas for further research are suggested.
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References
Panche AN, Diwan AD, Chandra SR. Flavonoids: An overview. J Nutr Sci. 2016; 5:1-15.
Guven H, Arici A, Simsek O. Flavonoids in our foods: A short review. J Basic Clin Health Sci. 2019; 3:96-106.
Kopustinskiene DM, Jakstas V, Savickas A, BernatonieneJ. Flavonoids as anticancer agents. Nutrients. 2020; 12(2):457.
Singh M, Kaur M, Silakari O. Flavones: An important scaffold for medicinal chemistry. Eur J Med Chem. 2014; 84:206-239.
Raffa D, Maggio B, Raimondi MV, Plescia F, Daidone G. Recent discoveries of anticancer flavonoids. Eur J Med Chem. 2017; 142:213-228.
Kanadaswami C, Lee LT, Lee PP, Hwang JJ, Ke FC, Huang YT, Lee MT. The antitumor activities of flavonoids. In Vivo. 2005; 19(5):895-909.
Wang TY, Li Q, Bi KS. Bioactive flavonoids in medicinal plants: Structure, activity and biological fate. Asian J Pharm Sci. 2018; 13(1):12-23.
Wen L, Jiang Y, Yang J, Zhao Y, Tian M, Yang B. Structure, bioactivity, and synthesis of methylated flavonoids. Ann N Y Acad Sci. 2017; 1398(1):120-129.
Walle T. Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass? Sem Cancer Biol. 2007; 17(5):354-362.
Kawaii S, Ishikawa Y, Yoshizawa Y. Relationship between the structure of methoxylated and hydroxylated flavones and their antiproliferative activity in HL60 cells. Anticancer Res. 2018; 38(10):5679-5684.
Chan EWC, Soo OY, Tan YH, Wong SK, Chan HT. Nobiletin and tangeretin (citrus polymethoxyflavones): An overview on their chemistry, pharmacology and cytotoxic activities against breast cancer. J Chin Pharm Sci. 2020; 29(7):443-454.
Semwal RB, Semwal DK, Combrinck S, Trill J, Gibbons S, Viljoen A. Acacetin ‒ A simple flavone exhibiting diverse pharmacological activities. Phytochem Lett. 2019; 32:56-65.
Singh S, Gupta P, Meena A, Luqman S. Acacetin, a flavone with diverse therapeutic potential in cancer, inflammation, infections and other metabolic disorders. Food Chem Toxicol. 2020; 145:111708.
Chan EWC, Ng YK, Tan CY, Alessandro L, Wong SK, Chan HT. Diosmetin and tamarixetin (methylated flavonoids): A review on their chemistry, sources, pharmacology, and anticancer properties. J Appl Pharm Sci. 2021; 11(3):22-28.
Kwon HS, Ha TJ, Hwang SW, Jin YM, Nam SH, Park KH, Yang MS. Cytotoxic flavonoids from the whole plants of Chrysanthemum zawadskii Herbich var.latilobum Kitamura. J Life Sci. 2006; 16(5):746-749.
González-Trujano ME, Ventura-Martínez R, Chávez M, Díaz-Reval I, Pellicer F. Spasmolytic and antinociceptive activities of ursolic acid and acacetin identified in Agastache mexicana. Planta Med. 2012; 78(8):793-796.
Rauf A, Khan R, Khan H, Ullah B, Pervez S. Antipyretic and antinociceptive potential of extract/fractions of Potentilla evestita and its isolated compound, acacetin. BMC Compl Altern Med. 2014; 14(1):448.
Zou GA, Guo D, Zhao HQ, Aisa HA. Bioactive constituents of Ziziphora clinopodioides. Chem Nat Compd. 2015; 51(5):961-963.
Veitch NC, Elliott PC, Kite GC, Lewis GP. Flavonoid glycosides of the black locust tree, Robinia pseudoacacia (Leguminosae). Phytochem. 2010; 71(4):479-486.
Al-Hazimi HM and Basha RM. Phenolic compounds from various Artemisia species. J Chem Soc Pak. 1991; 13(4):277-289.
Liou CJ, Wu SJ, Chen LC, Yeh KW, Chen CY, Huang WC. Acacetin from traditionally used Saussurea involucrata Kar. et Kir. suppressed adipogenesis in 3T3-L1 adipocytes and attenuated lipid accumulation in obese mice. Front Pharmacol. 2017; 8:589.
Suksamrarn A, Chotipong A, Suavansri T, Boongird S, Timsuksai P, Vimuttipong S, Chuaynugul A. Antimycobacterial activity and cytotoxicity of flavonoids from the flowers of Chromolaena odorata. Arch Pharm Res. 2004; 27(5):507-511.
Lin LZ and Harnly JM. Identification of the phenolic components of chrysanthemum flower (Chrysanthemum morifolium Ramat). Food Chem. 2010; 120(1):319-326.
Kim EO, Oh JH, Lee SK, Lee JY, Choi SW. Antioxidant properties and quantification of phenolic compounds from safflower (Carthamus tinctorius L.) seeds. Food Sci Biotechnol. 2007; 16(1):71-77.
Yin J, Ma Y, Liang C, Gao J, Wang H, Zhang L. A systematic study of the metabolites of dietary acacetin in vivo and in vitro based on UHPLC-Q-TOF-MS/MS analysis. J Agric Food Chem. 2019; 67(19):5530-5543.
Wu X, Zhang S, Li X, Zhang F, Fan Y, Liu Q, Wan X, Lin T. Postharvest UV-B radiation increases enzyme activity, polysaccharide and secondary metabolites in honeysuckle (Lonicera japonica Thunb.). Ind Crops Prod. 2021; 171:113907.
Bramati L, Minoggio M, Gardana C, Simonetti P, Mauri P, Pietta P. Quantitative characterization of flavonoid compounds in rooibos tea Aspalathus linearis) by LC− UV/DAD. J Agric Food Chem. 2002; 50(20):5513-5519.
Khan AU and Gilani AH. Selective bronchodilatory effect of rooibos tea (Aspalathus linearis) and its flavonoid, chrysoeriol. Eur J Nutr. 2006; 45(8):463.
Goławska S, Łukasik I, Kapusta T, Janda B. Analysis of flavonoids content in alfalfa. Ecol Chem Eng A. 2010; 17(2-3):261-267.
Tai BH, Cuong NM, Huong TT, Choi EM, Kim JA, Kim YH. Chrysoeriol isolated from the leaves of Eurya ciliata stimulates proliferation and differentiation of osteoblastic MC3T3-E1 cells. J Asian Nat Prod Res. 2009; 11(9):817-823.
Kim YH, Lee YS, Choi EM. Chrysoeriol isolated from Eurya cilliata leaves protects MC3T3‐E1 cells against hydrogen peroxide‐induced inhibition of osteoblastic differentiation. J Appl Toxicol. 2010; 30(7):666-673.
Chen SM, Li CH, Zhu XR, Deng YM, Sun W, Wang LS, Chen FD, Zhang Z. The identification of flavonoids and the expression of genes of anthocyanin biosynthesis in the chrysanthemum flowers. Biol Plant. 2012; 56(3):458-464.
Hsu YL, Kuo PL, Lin CC. Acacetin inhibits the proliferation of Hep G2 by blocking cell cycle progression and inducing apoptosis. Biochem Pharmacol. 2004;67(5):823-829.
Shim HY, Park JH, Paik HD, Nah SY, Kim DS, Han YS. Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signalling and SAPK/JNK1/2-c-Jun activation. Mol Cells. 2007; 24(1):95-104.
Watanabe K, Kanno SI, Tomizawa A, Yomogida S, Ishikawa M. Acacetin induces apoptosis in human T cell leukaemia Jurkat cells via activation of a caspase cascade. Oncol Rep. 2012; 27(1):204-209.
Kim CD, Cha JD, Li S, Cha IH. The mechanism of acacetin-induced apoptosis on oral squamous cell carcinoma. Arch Oral Biol. 2015; 60(9):1283-1298.
Hsu YL, Kuo PL, Liu CF, Lin CC. Acacetin-induced cell cycle arrest and apoptosis in human non-small cell lung cancer A549 cells. Cancer Lett. 2004; 212(1):53-60.
Pan MH, Lai CS, Hsu PC, Wang YJ. Acacetin induces apoptosis in human gastric carcinoma cells accompanied by activation of caspase cascades and production of reactive oxygen species. J Agric Food Chem. 2005; 53(3):620-630.
Singh RP, Agrawal P, Yim D, Agarwal C, Agarwal R. Acacetin inhibits cell growth and cell cycle progression, and induces apoptosis in human prostate cancer cells: Structure-activity relationship with linarin and linarin acetate. Carcinogenesis. 2005; 26(4):845-854.
Fong Y, Shen KH, Chiang TA, Shih YW. Acacetin inhibits TPA‐induced MMP‐2 and u‐PA expressions of human lung cancer cells through inactivating JNK signalling pathway and reducing binding activities of NF‐κB and AP‐1. J Food Sci. 2010; 75(1):30-38.
Shen KH, Hung SH, Yin LT, Huang CS, Chao CH, Liu CL, Shih YW. Acacetin, a flavonoid, inhibits the invasion and migration of human prostate cancer DU145 cells viainactivation of the p38 MAPK signalling pathway. Mol Cell Biochem. 2010; 333:279-291.
Chien ST, Lin SS, Wang CK, Lee YB, Chen KS, Fong Y, Shih YW. Acacetin inhibits the invasion and migration of human non-small cell lung cancer A549 cells by suppressing the p38α MAPK signalling pathway. Mol Cell Biochem. 2011; 350:135-148.
Kim HR, Park CG, Jung JY. Acacetin (5,7-dihydroxy-4'-methoxyflavone) exhibits in vitro and in vivo anticancer activity through the suppression of NF-κB/Akt signalling in prostate cancer cells. Int J Mol Med. 2014; 33(2):317-324.
Salimi A, Roudkenar MH, Sadeghi L, Mohseni A, Seydi E, Pirahmadi N, Pourahmad J. Selective anticancer activity of acacetin against chronic lymphocytic leukaemia using both in vivo and in vitro methods: Key role of oxidative stress and cancerous mitochondria. Nutr Cancer.
; 68(8):1404-1416.
Sun F, Li D, Wang C, Peng C, Zheng H, Wang X. Acacetin‐induced cell apoptosis in head and neck squamous cell carcinoma cells: Evidence for the role of muscarinic M3 receptor. Phytother Res. 2019; 33(5):1551-1561.
Kang KR, Kim JS, Kim TH, Seo JY, Park JH, Lim JW, Yu SK, Kim HJ, Shin SH, Park BR, Kim CS. Inhibition of cell growth and induction of apoptosis by acacetin in FaDu human pharyngeal carcinoma cells. Int J Oral Biol. 2020; 45(3):107-114.
Prasad N, Sharma JR, Yadav UC. Induction of growth cessation by acacetin via β-catenin pathway and apoptosis by apoptosis inducing factor activation in colorectal carcinoma cells. Mol Biol Rep. 2020; 47(2):987-1001.
Shendge AK, Chaudhuri D, Mandal N. The natural flavones, acacetin and apigenin, induce Cdk-cyclin mediated G2/M phase arrest and trigger ROS-mediated apoptosis in glioblastoma cells. Mol Biol Rep. 2021; 48(1):539-549.
Yang Y, Zhou X, Xiao M, Hong Z, Gong Q, Jiang L, Zhou J. Discovery of chrysoeriol, a PI3K-AKT-mTOR pathway inhibitor with potent antitumor activity against human multiple myeloma cells in vitro. J Huazhong Univ Sci Technol [Med Sci]. 2010; 30(6):734-740.
Ninomiya M, Nishida K, Tanaka K, Watanabe K, Koketsu M. Structure-activity relationship studies of 5,7-dihydroxyflavones as naturally occurring inhibitors of cell proliferation in human leukaemia HL-60 cells. J Nat Med. 2013; 67(3):460-467.
Wei W, He J, Ruan H, Wang Y. In vitro and in vivocytotoxic effects of chrysoeriol in human lung carcinoma are facilitated through activation of autophagy, sub-G1/G0 cell cycle arrest, cell migration and invasion inhibition and modulation of MAPK/ERK signalling pathway. J BUON.
; 24(3):936-942.
Manthey JA, Guthrie N. Antiproliferative activities of citrus flavonoids against six human cancer cell lines. J Agric Food Chem. 2002; 50(21):5837-5843.
Amrutha K, Nanjan P, Shaji SK, Sunilkumar D, Subhalakshmi K, Rajakrishna L, Banerji A. Discovery of lesser-known flavones as inhibitors of NF-κB signalling in MDA-MB-231 breast cancer cells – A SAR study. Bioorg Med Chem Lett. 2014; 24(19):4735-4742.
Zhang Y, Li Z, Min Q, Palida A, Zhang Y, Tang R, Chen L, Li H. 8-Chrysoeriol, as a potential BCL- inhibitor, triggers apoptosis of SW1990 pancreatic cancer cells. Bioorg Chem. 2018; 77:478-484.
Takemura H, Nagayoshi H, Matsuda T, Sakakibara H, Morita M, Matsui A, Ohura T, Shimoi K. Inhibitory effects of chrysoeriol on DNA adduct formation with benzo[α]pyrene in MCF-7 breast cancer cells. Toxicology.2010; 274(1-3):42-48.
Takemura H, Uchiyama H, Ohura T, Sakakibara H, Kuruto R, Amagai T, Shimoi K. A methoxyflavonoid, chrysoeriol, selectively inhibits the formation of a carcinogenic estrogen metabolite in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2010; 118(1-2):70-76.
Tan KW, Li Y, Paxton JW, Birch NP, Scheepens A. Identification of novel dietary phytochemicals inhibiting the efflux transporter breast cancer resistance protein (BCRP/ABCG2). Food Chem. 2013; 138(4):2267-2274.
Min DY, Jung E, Ahn SS, Lee YH, Lim Y, Shin SY. Chrysoeriol prevents TNFα-induced Cyp19 gene expression via Egr-1 downregulation in MCF-7 breast cancer cells. Int J Mol Sci. 2020; 21(20):7523.
Li S, Lv Q, Sun X, Tang T, Deng X, Yin Y, Li L. Acacetin inhibits Streptococcus pneumoniae virulence by targeting pneumolysin. J Pharm Pharmacol. 2020; 72(8):1092-1100.
Hayashi K, Hayashi T, Arisawa M, Morita N. Antiviral agents of plant origin: Antiherpetic activity of acacetin. Antiviral Chem Chemother. 1993; 4(1):49-53.
Kwon EB, Kang MJ, Ryu HW, Lee S, Lee JW, Lee MK, Lee HS, Lee SU, Oh SR, Kim MO. Acacetin enhances glucose uptake through insulin-independent GLUT4 translocation in L6 myotubes. Phytomed. 2020; 68:153178.
Ha SK, Moon E, Lee P, Ryu JH, Oh MS, Kim SY. Acacetin attenuates neuroinflammation via regulation the response to LPS stimuli in vitro and in vivo. Neurochem Res. 2012; 37(7):1560-1567.
Kim HG, Ju MS, Ha SK, Lee H, Lee H, Kim SY, Oh MS. Acacetin protects dopaminergic cells against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuroinflammation in vitro and in vivo. Biol Pharm Bull. 2012; 35(8):1287-1294.
Chen WP, Yang ZG, Hu PF, Bao JP, Wu LD. Acacetin inhibits expression of matrix metalloproteinases via a MAPK‐dependent mechanism in fibroblast‐like synoviocytes. J Cell Mol Med. 2015; 19(8):1910-1915.
Asthana J, Mishra BN, Pandey R. Acacetin promotes healthy aging by altering stress response in Caenorhabditis elegans. Free Radic Res. 2016; 50(8):861-874.
Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ. Effects and possible mechanisms of action of acacetin on the behaviour and eye morphology of Drosophila models of Alzheimer’s disease. Sci Rep. 2015; 5:16127.
Carballo‐Villalobos AI, González‐Trujano ME, López‐Muñoz FJ. Evidence of mechanism of action of anti‐inflammatory/antinociceptive activities of acacetin. Eur J Pain. 2014; 18(3):396-405.
Shahidi F, Ramakrishnan VV, Oh WY. Bioavailability and metabolism of food bioactives and their health effects: A review. J Food Bioact. 2019; 8:6-41.
Barreca D, Mandalari G, Calderaro A, Smeriglio A, Trombetta D, Felice MR, Gattuso G. Citrus flavones: An update on sources, biological functions, and health promoting properties. Plants. 2020; 9(3):288.
Ramirez G, Zamilpa A, Zavala M, Perez J, Morales D, Tortoriello J. Chrysoeriol and other polyphenols from Tecoma stans with lipase inhibitory activity. J Ethnopharmacol. 2016; 185:1-8.
Krishnan B, Ganesan AR, Balasubramani R, Nguyen DD, Chang SW, Wang S, Xiao J, Balasubramanian B. Chrysoeriol ameliorates hyperglycaemia by regulating the carbohydrate metabolic enzymes in streptozotocin-induced diabetic rats. Food Sci Hum Wellness. 2020; 9(4):236-354.
Bashyal P, Parajuli P, Pandey RP, Sohng JK. Microbial biosynthesis of antibacterial chrysoeriol in recombinant Escherichia coli and bioactivity assessment. Catalysts. 2019; 9(2):112.
Choi DY, Lee JY, Kim MR, Woo ER, Kim YG, Kang KW. Chrysoeriol potently inhibits the induction of nitric oxide synthase by blocking AP-1 activation. J Biomed Sci. 2005; 12(6):949-959.
Wu JY, Chen YJ, Bai L, Liu YX, Fu XQ, Zhu PL, Li JK, Chou JY, Yin CL, Wang YP, Bai JX. Chrysoeriol ameliorates TPA-induced acute skin inflammation in mice and inhibits NF-κB and STAT3 pathways. Phytomed. 2020; 68:153173.
Yoon HS and Park CM. Chrysoeriol ameliorates COX-2 expression through NF-κB, AP-1 and MAPK regulation via the TLR4/MyD88 signalling pathway in LPSstimulated murine macrophages. Exper Ther Med. 2021; 22(1):1-6.
Limboonreung T, Tuchinda P, Chongthammakun S. Chrysoeriol mediates mitochondrial protection viaPI3K/Akt pathway in MPP+
treated SH-SY5Y cells. Neurosci Lett. 2020; 714:134545.
Yokozawa T, Chen CP, Dong E, Tanaka T, Nonaka GI, Nishioka I. Study on the inhibitory effect of tannins and flavonoids against the 1,1-diphenyl-2-picrylhydrazyl radical. Biochem Pharmacol. 1998; 56(2):213-222.
Lai S, Chen JN, Huang HW, Zhang XY, Jiang HL, Li W, Wang PL, Wang J, Liu FN. Structure activity relationships of chrysoeriol and analogs as dual c-Met and VEGFR2 tyrosine kinase inhibitors. Oncol Rep. 2018; 40(3):1650-1656.